Combination treatment with pioglitazone and fenofibrate attenuates pioglitazone-mediated acceleration of bone loss in ovariectomized rats

Peroxisome proliferator-activated receptor (PPAR) g agonists, such as pioglitazone (Pio), improve glycemia and lipid profile but are associated with bone loss and fracture risk. Data regarding bone effects of PPARa agonists (including fenofibrate (Feno)) are limited, although animal studies suggest that Feno may increase bone mass. This study investigated the effects of a 13-week oral combination treatment with Pio (10 mg/kg per day)CFeno (25 mg/kg per day) on body composition and bone mass parameters compared with Pio or Feno alone in adult ovariectomized (OVX) rats, with a 4-week bone depletion period, followed by a 6-week treatment-free period. Treatment of OVX rats with PioCFeno resulted in w50% lower fat mass gain compared with Pio treatment alone. Combination treatment with PioCFeno partially prevented Pio-induced loss of bone mineral content (w45%) and bone mineral density (BMD; w60%) at the lumbar spine. Similar effects of treatments were observed at the femur, most notably at sites rich in trabecular bone. At the proximal tibial metaphysis, concomitant treatment with PioCFeno prevented Pio exacerbation of ovariectomy-induced loss of trabecular bone, resulting in BMD values in the PioCFeno group comparable to OVX controls. Discontinuation of Pio or Feno treatment of OVX rats was associated with partial reversal of effects on bone loss or bone mass gain, respectively, while values in the PioCFeno group remained comparable to OVX controls. These data suggest that concurrent/dual agonism of PPARg and PPARa may reduce the negative effects of PPARg agonism on bone mass.